Unconventional Signaling Modes

FZDs—similar to conventional GPCRs—undergo WNT-induced internalization and recycling [66, 82] ; which could be a means of rapid and transient desensitization and internalization- dependent signaling [ 83]. In the case of WNT signaling, endocytosis was also proposed as a means to establish mor-

phogen gradients in the developing embryo [84] . As discussed recently [85] , the role of endocytosis for WNT/FZD signaling remains rather unclear. Important players are again DVL and P-arrestin interacting with the clathrin adaptor protein-2 [86, 87] . Results from our group indicate that inhibition of endocytosis by hyperosmolaric sucrose and K+ depletion leads to inhibition of WNT-3A-induced P-catenin signaling by rapid downregulation of DVL rather than by inhibition of receptor internalization [88]. The mechanism of the sucrose-induced degradation of DVL is not understood yet but may constitute a negative feedback loop involving the regulation of DVL stability, possibly in relation to agonist-dependent receptor dynamics.

Another layer of signaling complexity on the level of receptor dynamics was recently described in the Drosophila neuromuscular junction, where wingless activates FZD2 resulting in internalization and C-terminal proteolysis of the receptor. The C-terminus is then translocated to the nucleus where it regulates gene transcription. This exciting signaling mode is awaiting confirmation in a mammalian setting. It will be important to delineate if this is a general signaling feature of other FZDs.

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